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KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy

1
Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary
2
Department of Tumor Biology, National Koranyi Institute of Pulmonology–Semmelweis University, 1122 Budapest, Hungary
3
Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, 45239 Essen, Germany
42
nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary
5
Tumor Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, 1091 Budapest, Hungary
68
th Department of Pulmonology, National Koranyi Institute of Pulmonology, 1122 Budapest, Hungary
7
MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, 1091 Budapest, Hungary
8
Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University Vienna, A-1090 Vienna, Austria
*
Authors to whom correspondence should be addressed.
Equal contribution.
Cancers 2019, 11(10), 1514; https://doi.org/10.3390/cancers11101514
Received: 27 August 2019 / Revised: 23 September 2019 / Accepted: 3 October 2019 / Published: 9 October 2019
Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.
Keywords: bevacizumab; non-small-cell lung cancer; advanced-stage lung adenocarcinoma; platinum-based chemotherapy; KRAS mutation bevacizumab; non-small-cell lung cancer; advanced-stage lung adenocarcinoma; platinum-based chemotherapy; KRAS mutation
MDPI and ACS Style

Ghimessy, A.K.; Gellert, A.; Schlegl, E.; Hegedus, B.; Raso, E.; Barbai, T.; Timar, J.; Ostoros, G.; Megyesfalvi, Z.; Gieszer, B.; Moldvay, J.; Renyi-Vamos, F.; Lohinai, Z.; Hoda, M.A.; Klikovits, T.; Klepetko, W.; Laszlo, V.; Dome, B. KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy. Cancers 2019, 11, 1514.

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